This invention relates to a liquid crystal form of the cyclic peptide cyclosporin and to powder formulations of cyclosporin prepared using this novel liquid crystal form of the drug. Methods for preparing and using these formulations are also provided. In particular, the present invention relates to dispersible spray dried particles of cyclosporin suitable for pulmonary delivery.
The cyclosporins are a group of non-polar oligopeptides with immunosuppressant activity. Cyclosporin A, also known as cyclosporine, is the major known cyclosporin, with the structure of cyclosporins B through I also being known (The Merck Index, Twelfth Edition, 464-465 (1996)). A number of synthetic cyclosporin analogs have been prepared. (Id.)
Cyclosporin A is an orally active immunosuppressive drug that has been used for immune suppression since the mid-1980""s (Guzman et al., J. of Pharm Sci, 82:5) 496-506 (1993)). It has become the mainstay of organ transplant therapy as prophylaxis against organ rejection. The original cyclosporine product for this use, Sandimmune by Sandoz, is formulated in corn oil and designed for oral delivery, however, bioavailability from the gastrointestinal tract tends to be low and somewhat erratic. (Id.) Recently, Sandoz has begun marketing an improved proprietary oral formulation (Neoral) that is claimed to be more reliable than the original (Med. Ad. News, Feb 1996, 7-10). Cyclosporin A causes kidney and liver toxicity at high doses when delivered orally and tolerability must always be monitored along with clinical assessments of rejection (Physician""s Desk Reference, 52nd Ed, 1891-1901 (1998)).
In order to avoid the complications associated with oral delivery, and, in particular, to prevent lung transplant rejection, it may be desirable to deliver cyclosporin directly to the lungs. In fact, nebulized cyclosporin A appears to be efficacious in preventing lung transplant rejection using aerosolized liquid ethanol and polyethylene glycol cyclosporine formulations (Burckart, et al., Inhalation Delivery of Therapeutic Peptides and Proteins, Marcel Dekker, N.Y., pp 281-299 (1997)). Nebulized cycisporin A also appears to lower oral cortico-steroid dependency in asthma (Morley, et al., Cyclosporin Form for Pulmonary Administration, European Patent Application No. 92104426.9 (1992)). Liposomal cyclosporine has also been administered as an aerosol using a nebulizer (Waldrep, et al., Cyclosporin A Liposome Aerosol: Particle Size and Calculated Respiratory Deposition, Intl. J. Pharm. 97:205-212 (1993)). The aim of such formulations has been to decrease toxicity compared to conventional oral formulations and to provide an alternative to nebulized solutions containing cosolvents.
Nebulized solution delivery of cyclosporin suffers from limited drug solubility in aqueous based vehicles. Further, there are safety concerns surrounding nebulization of organic vehicles. Delivery of nebulized solutions and suspensions both suffer from low drug delivery efficiency from commercial nebulizers. Aerosolization of cyclosporin A (CsA) with MDI""s would involve a solution of CsA in propellant(s) (chlorofluorocarbon or non-chlorofluorocarbon propellants) or the use of finely divided CsA suspended in propellant(s). Poor drug delivery efficiency and low drug-carrying payload capacity make MDI""s an inconvenient means of aerosol delivery for human dosing regimens that may require 1 mg to 20 mg of CsA delivered per day to the lung.
In view of the difficulty of delivering a solution of cyclosporin by inhalation, it may be desirable to deliver cyclosporin as a dry powder. The ability to deliver pharmaceutical compositions as dry powders, however, is problematic in certain respects. The dosage of many pharmaceutical compositions is often critical, so it is desirable that dry powder delivery systems be able to accurately, precisely and reliably deliver the intended amount of drug. It is also essential that dry powders for pulmonary delivery be readily dispersible in order to assure adequate distribution and systemic absorption. Because CsA can cause gingivitis, it is important that oropharyngeal deposition be minimized.
The present invention provides a novel liquid crystal form of cyclosporin not previously known. This novel form is thermotropic liquid crystal cyclosporin. It has unexpectedly been found that spray drying organic solutions containing cyclosporin, in particular cyclosporin A (CsA), under specific conditions, results in this novel form of cyclosporin. Spray drying of organic solutions containing cyclosporin produces powders where the particulate cyclosporin exhibits a lack of 3-dimensional (3-d) order as determined by powder X-ray diffraction (PXRD) and also exhibits 2-d order when analyzed by small angle X-ray scattering (SAXS). Further, it exhibits a phase change from solid to liquid over a narrow temperature range with a step-wise change in heat capacity, i.e., a glass transition-like melt. This form of cyclosporin is liquid crystal cyclosporin. The process conditions for spray drying may be varied within certain limits to achieve very narrow particle size distributions that make the powders especially suitable for efficient delivery by oral inhalation. These powders have high delivery efficiency when aerosolized with a dry powder inhaler and have demonstrated physical, chemical, and aerosol stability over prolonged periods of high temperature and high humidity.
In one aspect the invention provides liquid crystal cyclosporin. In particular, the liquid crystal form of cyclosporin A is provided.
In another aspect the invention provides dispersible powder formulations of liquid crystal cyclosporin for pulmonary delivery. In particular, cyclosporin-based dispersible powder formulations which are spray dried from cyclosporin and, optionally, excipient, in a solvent are provided, as are methods for making these formulations. Spray dried cyclosporin A powders are specifically provided.
In a further aspect the invention provides methods for treating a subject suffering from or subject to a condition which may be alleviated or prevented by the administration of cyclosporin comprising administering the dispersible powder cyclosporin formulations described above. In particular, methods to alleviate or prevent lung diseases or conditions which affect the lung are provided. Cyclosporin may be used as an anti-inflammatory, immunosuppressive or anti-asthmatic agent.